Consensus chemistry and R-turn conformation of the active core of the insect kinin neuropeptide family

Abstract

Each residue of the insect kinin carboxy-terminal pentapeptide has a distinct role in conformational preference, specific receptor interactions or signal transduction. The beta-turn preference of residues Phe1-X2-X3-Trp4 implicates this as the bioactive conformation. The amidated carboxyl terminus, required for activity in many neuropeptide families, may be generally important for signal transduction and its inclusion may therefore be essential for agonist design.

Receptor assay guided structure‐activity studies of helicokinin insect neuropeptides and peptidomimetic analogues

“…In agreement with already published structure‐activity data of kinins20 an alanine scan established Phe 2 and Gly 6 CONH 2 as the most important residues in helicokinin I followed by Trp 5 , which shows a reduced receptor activation by a factor of 25–30. The significance of the indole side‐chain of tryptophan is underlined by the inactive phenylalanine analogue 36 .…”

“…Pentapeptide Phe‐Ser‐Pro‐Trp‐Gly‐CONH 2 ( 5 ) induced only a slightly reduced fluid secretion in the Malphigian tubules in agreement with published data on truncated kinins from other insect species20. However, the activity in the receptor assay was reduced by a factor of more than 100 indicating that the N ‐terminal tyrosine and thus the complete hexapeptide is essential for full receptor activation.…”

“…As already established for other C ‐terminal kinin pentapeptides, helicokinin pentapeptide 5 showed only a slightly reduced secretion rate in the Malphigian tubule assay20. A significantly lower activity (factor 120) was detected in the receptor assay.…”

“…Noteworthy, the stereochemistry of Ser 3 and Pro 4 turned out to be much more important for receptor activation than the nature of the side‐chain. Based on NMR measurements in aqueous solutions a C ‐terminal β‐turn was found for several kinins20 and has been suggested to be essential for receptor binding. D ‐amino acids are well known for their turn‐inducing effects and are expected to shift or to destabilize the relevant C ‐terminal β‐turn in positions 3 and 4 resulting in a considerable loss of activity.…”

An antidiuretic peptide (Tenmo-ADFb) with kinin-like diuretic activity on Malpighian tubules of the house cricket, Acheta domesticus (L.)

“…The minimal sequence requirement for diuretic activity is a C-terminal amidated pentapeptide (Phe-Xxx 1 -Xxx 2 -Trp-Gly-NH 2 ; where X 1 is Asn, His, Ser, Tyr or Phe, and X 2 is Ala, Pro or Ser) (Coast et al, 1990). Within this 'active core', residues one (Phe), four (Trp) and five (Gly-NH 2 ) are invariant, and both Phe and Trp are essential for activity (Roberts et al, 1997). In the active conformation, the two aromatic residues are brought into close proximity on one surface of the molecule, which adopts a type VI ␤-turn (Nachman et al, 2002).…”